E72653c3-6208-4281-85b4-b6db84b746bd - samples
Ontology highlight
ABSTRACT:
PROVIDER: EGAD00001012841 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:This dataset contains 15 single-cell RNA sequencing samples from 6 CML patients before and after TKI-cessation. The raw data is available as fastq files.
| EGAD00001012842 | EGA
Project description:An approximately 60% of chronic myeloid leukemia (CML) patients who achieved a deep molecular response for more than 2 years maintained a major molecular response after discontinuation of imatinib. These findings indicate the possibility that a portion of CML patients treated with Tyrosine kinase inhibitors (TKIs) could discontinue TKI therapy, although long-term prognosis and/or adverse events after TKIs cessation remain unclear. Recent reports showed that transient musculoskeletal pain occurs in approximately 30% of CML patients after stopping imatinib. To ascertain the factors underlying musculoskeletal events after TKI cessation, we investigated exosomal miRNA in five CML patients who did not experience musculoskeletal events and five patients with musculoskeletal pain after stopping TKIs.
2016-12-15 | GSE85903 | GEO
Project description:To study the innate and adaptive immune responses in CML, we profiled 25 samples from CML patients including samples at diagnosis (n = 7, N = 9, where n is the number of subjects and N the number of samples if different from n) and before and after TKI-cessation with imatinib (n = 6, N = 15) with paired single-cell RNA and T cell receptor (TCR) αβ chain sequencing (scRNA+TCRαβ-seq) and compared our data to different cancers (n = 29) and healthy donors (n = 7). This dataset contains the samples from before and after TKI-cessation, please see the manuscript for info related to the other datasets.
| EGAS00001005044 | EGA
Project description:Tyrosine kinase inhibitors (TKI) are highly effective in treating chronic myelogenous leukemia (CML), but primitive, quiescent CML stem cells persist as a source for recurrence. The effects of TKI treatment on CML stem cell metabolism, and the role of metabolic reprogramming in CML stem cell persistence after TKI treatment are not clear. Here we show that TKI treatment in a CML mouse model leads to acute inhibition of aerobic glycolysis, glutaminolysis, TCA cycle and oxidative phosphorylation (OXPHOS) in CML progenitor cells, but that these pathways are restored with continued TKI treatment. Single cell analysis reveals that primitive CML stem cell subpopulations characterized by lower OXPHOS, glycolysis, nucleotide metabolism, and MYC gene signatures are enriched after TKI treatment. TKI treatment initially results in broad inhibition of energy metabolism gene signatures, but continued treatment leads to metabolic reprogramming in persistent stem cells, with enhanced OXPHOS and MYC gene signatures. TKI treatment enhanced HIF-1 activity in quiescent CML stem cells, and addition of a HIF-1 inhibitor significantly depleted CML stem cells in TKI-treated mice. Our results identify mechanisms of metabolic adaptation in CML stem cells following TKI treatment, which can be targeted to deplete persistent quiescent CML stem cells.
2023-08-30 | GSE207346 | GEO
Project description:Properties of cancer stem cells (CSC) involved in drug-resistance and relapse have significant effect on clinical outcome. Although tyrosine kinase inhibitors (TKIs) have dramatically improved survival of patients with chronic myelogenous leukemia (CML), TKIs have not fully cure CML due to TKI-resistant CML stem cells. Moreover, the relapse after discontinuation of TKIs has not been predicted in CML patients with best TKI-response. In our study, pre-hematoopoietic progenitor cells (pre-HPCs), a model of CML stem cells derived from CML-iPSCs identified a novel antigen of TKI-resistant CML cells. Even in the fraction reported as TKI-sensitive, the antigen+ cells showed TKI-resistance in CML patients. In addition, residual CML cells in patients with optimal TKI-response were concentrated in the antigen+ population.
2016-12-21 | GSE92624 | GEO
Project description:Tyrosine kinase inhibitors (TKI) are highly effective in treatment of chronic myeloid leukemia (CML) but do not eliminate leukemia stem cells (LSC), which remain a potential source of relapse. TKI treatment effectively inhibits BCR-ABL kinase activity in CML LSC, suggesting that additional kinase-independent mechanisms contribute to LSC preservation. We investigated whether signals from the bone marrow (BM) microenvironment protect CML LSC from TKI treatment. Coculture with human BM mesenchymal stromal cells (MSC) significantly inhibited apoptosis and preserved CML stem/progenitor cells following TKI exposure, maintaining colony forming ability and engraftment potential in immunodeficient mice. We found that the N-Cadherin receptor plays an important role in MSC-mediated protection of CML progenitors from TKI. N-Cadherin-mediated adhesion to MSC was associated with increased cytoplasmic N-Cadherin-β-catenin complex formation, as well as enhanced β-catenin nuclear translocation and transcriptional activity. Increased exogenous Wnt-mediated β-catenin signaling played an important role in MSC-mediated protection of CML progenitors from TKI treatment. Our results reveal a close interplay between N-Cadherin and the Wnt-β-catenin pathway in protecting CML LSC during TKI treatment. Importantly, these results reveal novel mechanisms of resistance of CML LSC to TKI treatment, and suggest new targets for treatment designed to eradicate residual LSC in CML patients.
2013-01-01 | GSE43225 | GEO
Project description:To elucidate whether tyrosine kinase inhibitor (TKI) resistance in CML is associated with characteristic genomic alterations, we analyzed DNA samples from 45 TKI resistant CML patients with 250K single nucleotide polymorphism (SNP) arrays. From 20 patients, matched serial samples of pre-treatment and TKI resistance time points were available. 11 of the 45 TKI resistant patients had mutations of BCR-ABL1, including two T315I mutations. Besides known TKI resistance associated genomic lesions such as duplication of the BCR-ABL1 gene (n=8) and trisomy 8 (n=3), recurrent submicroscopic alterations including acquired uniparental disomy were detectable on chromosomes 1, 8, 9, 17, 19 and 22. On chromosome 22, newly acquired and recurrent deletions of the IGLC1 locus were detected in three patients, who had previously presented with lymphoid or myeloid blast crisis. This may support a hypothesis of TKI induced selection of subclones differentiating into immature B-cell progenitors as a mechanism of disease progression and evasion of TKI sensitivity. Keywords: SNP-chip
2010-02-09 | GSE18964 | GEO
Project description:Leukemic stem cells (LSCs) can acquire non-mutational resistance following drug treatment leading to therapeutic failure and relapse. However, oncogene-independent mechanisms of drug persistence in LSCs are incompletely understood, which is the primary focus of this study. We integrated proteomics, transcriptomics, and metabolomics to determine the contribution of STAT3 in promoting metabolic changes in tyrosine kinase inhibitor (TKI) persistent chronic myeloid leukemia (CML) cells. Proteomic and transcriptional differences in TKI persistent CML cells revealed BCR-ABL-independent STAT3 activation in these cells. While knockout of STAT3 inhibited the CML cells from developing drug-persistence, inhibition of STAT3 using a small molecule inhibitor sensitized the persistent CML cells to TKI treatment. Interestingly, given the role of phosphorylated STAT3 as a transcription factor, it localized uniquely to genes regulating metabolic pathways in the TKI-persistent CML stem and progenitor cells. Subsequently, we observed that STAT3 dysregulated mitochondrial metabolism forcing the TKI-persistent CML cells to depend on glycolysis, unlike TKI-sensitive CML cells, which are more reliant on oxidative phosphorylation. Finally, targeting pyruvate kinase M2, a rate-limiting glycolytic enzyme, specifically eradicated the TKI-persistent CML cells. By exploring the role of STAT3 in altering metabolism, we provide critical insight into identifying potential therapeutic targets for eliminating TKI-persistent LSCs.
2021-07-06 | GSE174800 | GEO
Project description:Leukemic stem cells (LSCs) can acquire non-mutational resistance following drug treatment leading to therapeutic failure and relapse. However, oncogene-independent mechanisms of drug persistence in LSCs are incompletely understood, which is the primary focus of this study. We integrated proteomics, transcriptomics, and metabolomics to determine the contribution of STAT3 in promoting metabolic changes in tyrosine kinase inhibitor (TKI) persistent chronic myeloid leukemia (CML) cells. Proteomic and transcriptional differences in TKI persistent CML cells revealed BCR-ABL-independent STAT3 activation in these cells. While knockout of STAT3 inhibited the CML cells from developing drug-persistence, inhibition of STAT3 using a small molecule inhibitor sensitized the persistent CML cells to TKI treatment. Interestingly, given the role of phosphorylated STAT3 as a transcription factor, it localized uniquely to genes regulating metabolic pathways in the TKI-persistent CML stem and progenitor cells. Subsequently, we observed that STAT3 dysregulated mitochondrial metabolism forcing the TKI-persistent CML cells to depend on glycolysis, unlike TKI-sensitive CML cells, which are more reliant on oxidative phosphorylation. Finally, targeting pyruvate kinase M2, a rate-limiting glycolytic enzyme, specifically eradicated the TKI-persistent CML cells. By exploring the role of STAT3 in altering metabolism, we provide critical insight into identifying potential therapeutic targets for eliminating TKI-persistent LSCs.
2021-07-06 | GSE152706 | GEO
Project description:Leukemic stem cells (LSCs) can acquire non-mutational resistance following drug treatment leading to therapeutic failure and relapse. However, oncogene-independent mechanisms of drug persistence in LSCs are incompletely understood, which is the primary focus of this study. We integrated proteomics, transcriptomics, and metabolomics to determine the contribution of STAT3 in promoting metabolic changes in tyrosine kinase inhibitor (TKI) persistent chronic myeloid leukemia (CML) cells. Proteomic and transcriptional differences in TKI persistent CML cells revealed BCR-ABL-independent STAT3 activation in these cells. While knockout of STAT3 inhibited the CML cells from developing drug-persistence, inhibition of STAT3 using a small molecule inhibitor sensitized the persistent CML cells to TKI treatment. Interestingly, given the role of phosphorylated STAT3 as a transcription factor, it localized uniquely to genes regulating metabolic pathways in the TKI-persistent CML stem and progenitor cells. Subsequently, we observed that STAT3 dysregulated mitochondrial metabolism forcing the TKI-persistent CML cells to depend on glycolysis, unlike TKI-sensitive CML cells, which are more reliant on oxidative phosphorylation. Finally, targeting pyruvate kinase M2, a rate-limiting glycolytic enzyme, specifically eradicated the TKI-persistent CML cells. By exploring the role of STAT3 in altering metabolism, we provide critical insight into identifying potential therapeutic targets for eliminating TKI-persistent LSCs.
2021-07-06 | GSE152701 | GEO